Aminoalkylations of CH-acidic compounds have been known for about 100 years. They are referred to as Mannich reactions and are one of the most important C—C bond forming reactions of organic chemistry.

In its original and most well-known form, the Mannich reaction is carried out with three reactants in the form of a “three-component coupling”: an enolizable ketone, a nonenolizable aldehyde (frequently formaldehyde or an arylaldehyde) and an amine component (ammonia or a primary or secondary amine) react with one another to form a β-aminoketone. In this “Mannich base” the active hydrogen of the enolizable ketone has been replaced by an aminoalkyl substituent. This direct variant of the Mannich reaction is particularly industrially attractive, because the three reactants specified are usually readily available and inexpensive, and at least very easily obtainable. Also, these reactants are generally not sensitive (i.e., have good storability) and therefore allow simple handling. Finally, the direct three-component coupling of commercially available reactants is a single-stage, i.e., the shortest conceivable, synthesis of β-aminoketones.
In addition, there are less industrially attractive indirect variants of the Mannich reaction in which preformed enolate equivalents (usually enamines or silyl enol ethers) are used. These compounds are generally not commercially available or are expensive. Their preceding preparation is an additional synthetic step. Also, the trimethylsilyl enol ethers in particular and, to a lesser extent, the enamines, are acid- and hydrolysis-sensitive, poorly storable and difficult to handle. Although silyl enol ethers having certain other silyl groups are more stable, they are more expensive to prepare. The high nucleophilicity of the preformed enolate equivalents has advantages and disadvantages. On the one hand, it allows frequently mild reaction conditions and thus occasionally makes possible Mannich reactions that in the direct variant are accompanied by too many secondary reactions. On the other hand, the aminomethylations of preformed enolate equivalents are frequently low temperature reactions and therefore costly and inconvenient on the industrial scale. Further disadvantages of stereoselective variants using preformed enolate equivalents are the use of industrially problematic Lewis acid catalysts, poor solubilities of reaction components at the low temperature and, for this reason, the necessity of using large amounts of solvent (poor space/time yields) or the use of problematic or expensive solvents. Iminium salts in the Mannich reaction are distinctly more reactive (more electrophilic) than imines. This brings advantages and disadvantages that are similar to those described above for preformed enol equivalents.
Asymmetric Mannich reactions are described, for example, in M. Arend et al. (Angew. Chem. Int. Ed. Engl. 1998, 37, 1045–1070), which states on page 1067: “Despite many studies, and some notable successes, penetration into enantiomerically pure Mannich bases is still only beginning. [ . . . ] When one thinks of the many in situ racemization-free routes to derivatization of the kinetic products (to, for example, amino alcohols, diamines, amines etc.), it becomes understandable that the possibility of developing efficient and effective routes to products of controlled absolute configuration may indeed be realizable. Catalytic processes, which are established in many other areas of stereochemisty, are almost completely untouched”.
The use of stoichiometric amounts of chiral auxiliaries in an asymmetric Mannich reaction is described, for example, by H. Ishitani et al. (J. Am. Chem. Soc. 2000, 122, 8180–8186). This method has no industrial relevance, since the chiral auxiliary is covalently bonded to the preformed imine (or more rarely to the preformed enolate equivalent), in order to conduct the Mannich reaction as a diastereoselective addition. Synthesis, linking and, after completed Mannich reaction, removal of the chiral auxiliary require a plurality of additional synthetic steps. The Mannich additions were in addition frequently low temperature reactions, and the chiral auxiliaries were difficult to obtain or only available in an absolute configuration.
Catalytic asymmetric Mannich variants were summarized by S. E. Denmark & O. J.-C. Nicaise (“Catalytic Enantioselective Mannich-Type Reactions” in Comprehensive Asymmetric Catalysis, E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer-Verlag: New York, 1999; Vol. 2, Chapter 26.2.9; pages 954–958). The catalytic variants are for the most part indirect Mannich reactions that limits their industrial attractiveness. Also, complicated chiral transition metal catalysts have to be used.
Direct asymmetric three-component Mannich reactions using unmodified ketones can be induced by heteropolymetallic chiral catalysts based on lanthanides, although, as described in S. Yamasaki et al. (Tetrahedron Left. 1999, 40, 307–310), result in only moderate chemical yields (≦16%) and enantiomeric excesses (<64% ee).
The first direct catalytic asymmetric three-component Mannich reaction which comes near to fulfilling the industrial demands was reported only recently (B. List, J. Am. Chem. Soc. 2000, 122, 9336–9337; cf. H. Gröger & J. Wilken, Angew. Chem. Int. Ed. Engl. 2001, 40, 529–532). In this reaction, unmodified ketones are reacted with aryl- or alkylaldehydes and certain aniline derivatives with catalysis using 35 mol % of (L)-proline in dimethyl sulfoxide or chloroform at room temperature to give optically active Mannich bases. The chemical yields were moderate to good (35–90%), and the optical purities average to very good (73–96% ee).
Mannich bases and their derivatives have numerous industrial applications that are summarized in M. Arend et al. (Angew. Chem. Int. Ed. Engl. 1998, 37, 1044–1070) on page 1045. The most important field of use, in particular of chiral Mannich bases, is the preparation of active ingredients for drugs, for example the neuroleptic Moban. On this subject, it is stated in Arend et al. on page 1047: “The classical Mannich reaction is not suited to the enantioselective synthesis of β-amino ketones and amino aldehydes. Thus, the majority of pharmaceutical products, which are derived from the Mannich reaction, are used in the form of racemates. The application of enantiomerically pure Mannich bases is only possible when these are available by separation of the racemate. This problem becomes more severe when one takes into consideration the increasing importance of stereochemically pure pharmaceuticals (the avoidance of “isomer ballast” and of undesirable side effects).”
Racemic β-aminoketones that can be described by a mixture of a compound of formula (A) and its enantiomer
    wherein R1 is phenyl, R2 is H, R3 is phenyl, R4 is methyl and R5 is phenyl, are described in T. Akiyama et al., Synlett 1999, 1045–1048;    wherein R1 is p-tolyl, R2 is H, R3 is p-methoxycarbonylphenyl, R4 is methyl and R5 is phenyl are described in N. Shida et al, Tetrahedron Left. 1995, 36, 5023–5026;    wherein R1 is phenyl, R2 is H, R3 is p-chlorophenyl, R4 is methyl and R5 is phenyl are described in CA120: 257988; and    wherein R1 is tert-butyl or phenyl, R2 is R3 is R4 is methyl and R5 is phenyl are described in E. G., Nolen et al., Tetrahedron Lett. 1991, 32, 73–74.
Chiral 1,3-amino alcohols, like, for example, the analgesic tramadol, are important as active pharmaceutical ingredients, and also as chiral auxiliaries for asymmetric syntheses, documented, for example, in S. Cicchi et al. (“Synthesis of new enantiopure β-amino alcohols: their use as catalysts in the alkylation of benzaldehyde by diethylzinc”, Tetrahedron: Asymmetry 1997, 8, 293–301).
The limited diastereoselective reduction of Mannich bases with LiAlH4 was described as early as 1985 by J. Barluenga et al. (“Diastereoselective synthesis of β-amino alcohols with three chiral centers by reduction of β-amino ketones and derivatives” J. Org. Chem. 1985, 50, 4052–4056).
A multistage enzymatic method for producing chiral 1,3-amino alcohols starting from racemic butane-1,4-diols is described in the U.S. Pat. No. 5,916,786.
The carbonyl reduction of α-chiral β-aminoketones using LiAlH4 (lithium aluminum hydride) or with hydrogen in the presence of platinum catalysts results preferentially in the 1,3-amino alcohol dia-(B) whose hydroxy configuration is diastereomeric to formula (B) when the amino substituent is tertiary
and an approximately equimolar mixture of the diastereomers (B) and dia-(B) results when the amino substituent is secondary (M.-J. Brienne et al., Bull. Soc. Chim. France 1969, 2395; A. Andrisano & L. Angiolini Tetrahedron 1970, 26, 5247).
Chiral 1,3-amino alcohols of formula (B) could hitherto not be prepared with industrially usable diastereoselectivities from Mannich bases of formula (A).
The patent application EP 1117645 (published as WO 00/20392) describes optically active 1,3-amino alcohols of formula (B) wherein R1 is o-aminophenyl, R2 is H, R3 is 2-pyridyl, R4 is 2-pyridyl and R5 is phenyl or 3,5-dimethylisoxazol-4-yl that had previously been prepared by a classical optical resolution, and are useful as intermediate in the synthesis of are bile acid re-absorption inhibitors for the treatment of obesity and disorders of lipid metabolism. The compound of the formula (B) can be used in the synthesis of the compounds as described in Table 1 of WO 00/20392, e.g., the compound of the formula
as described In Example 9.